PROJECT SUMMARY Salmonella enterica serovar Typhimurium (Stm) causes a severe inflammatory diarrhea and infects an estimated 100 million patients per year. A number of studies have described mechanisms of expansion in mice post-antibiotic treatment which causes a disruption to the commensal microbial community and leads to enhanced susceptibility to enteric pathogens such as Stm and Clostridium difficile. However, Stm colonizes the gut in the absence of antibiotic treatment. Thus, it is important to study the mechanisms of Stm expansion in non-antibiotic treated hosts. Our central hypothesis is that specific members of the gut microbiota and associated metabolites facilitate Stm expansion in the distal gut of mice. In this regard, we found that Stm expands in the distal guts of 129Sv/J (129) mice but not in C57BL/6nramp1 (B6N) mice. Many mechanisms, which are largely uncharacterized, play a role in this process. We have shown previously that Stm expansion in the guts of B6N mice is controlled by Bacteroides spp., which are not present in 129 mice, and that Bacteroides-dependent production of the short chain fatty acid propionate is sufficient to limit Stm expansion in vitro and in vivo. The long-term goal of this research proposal is to identify the mechanisms by which Stm thrives in the distal gut and exploits host/commensal bacteria-derived metabolites to expand. In Aim 1, we will identify commensal bacteria-derived and immune factors that promote expansion of Stm in the distal gut of 129 mice. In Aim 2, we will identify and characterize Stm pathways required for expansion in the distal gut of non- antibiotic treated mice. The proposed work is innovative because it establishes new concepts on how a pathogen can exploit host and commensal bacteria-derived metabolites. It is our expectation that the outcome of this study will identify new mechanisms by which Stm, and likely other enteric pathogens, exploit specific gut environments and microbial communities to thrive, potentially leading to new methods of transmission control and to the rational design of therapeutics that will benefit public health.